Parkin Disease and the Lewy Body Conundrum

A clear pathologic hallmark like that identified in sporadic Parkinson’s disease (PD) is lacking in many of the monogenic causes of PD. In leucine-rich repeat kinase 2 (LRRK2) mutations (PARK8), alpha-synuclein pathology in the form of Lewy bodies (LBs) is frequently, but not consistently, observed. Other pathologies reported in LRRK2 cases include tau inclusions of the Alzheimer, progressive supranuclear palsy, and frontotemporal lobar degeneration types, and TAR DNA-binding protein 43 (TDP-43) inclusions. There has been only a single report of a compound heterozygous, phosphatase and tensin homolog (PTEN)-induced, putative kinase 1 (PINK1; PARK6) patient coming to autopsy. That patient presented with asymmetrical rigidity at age 31 years and had a good motor response to dopaminergic therapy, but died at age 39 years. Pathologic study revealed nigral neuronal loss and gliosis, with a few LBs and Lewy neurites identified in the substantia nigra (SN), nucleus basalis of Meynert (NBM), and reticular formation of the brainstem, but not in the locus coeruleus (LC), amygdala, or hippocampus. This finding is interesting, because PINK1 and parkin share a similar clinical phenotype, are believed to share a mechanistic pathway in the pathogenesis of PD, and, overwhelmingly, parkin-linked disease (PARK2) has been considered a non-LB disorder. Case reports of genetically confirmed parkin disease and our recent case series of 5 unrelated parkin compound heterozygotes describe the pathology of parkin disease as a severe nigropathy with LBs present in only a minority of patients. The LC is consistently affected by neuronal loss, and tau pathology is occasionally described but is not a significant feature. Miyakawa and colleagues describe the first homozygous parkin disease case with definite LB pathology at postmortem examination. The female patient developed gait difficulty at age 61 years, and examination revealed all the cardinal features of PD. She appeared to respond well to dopaminergic therapy and developed motor fluctuations after 7 years, which were managed with bilateral deep-brain stimulation of the subthalamic nuclei. Her parents were first cousins, and her mother also possibly was affected. She was homozygous for deletions of exons 2 through 4 of parkin. Neuropathologic examination after 11 years of disease revealed a depigmented SN and LC. Histopathologic study confirmed SN neuronal loss with LBs and Lewy neurites in various brainstem nuclei (SN, LC, dorsal motor nucleus of the vagus, and NBM), the amygdaloid nucleus, the striatum, and the anterior cingulate cortex without evidence of other significant pathologies. Those authors suggested that the presence of truncated parkin protein (assumed to result from the homozygous deletion) may have resulted in LB formation; and they also considered the older age of onset but eventually concluded that coexistent sporadic PD may have led to the pathologic changes described. There are several possible theories regarding the finding of LB pathology in both parkin and PINK1related disease. First, it is possible that the LBs identified in these patents represent incidental LB disease (iLBD), which is described on postmortem examination in controls of increasing age, ie, the LBs represent presymptomatic PD, but the parkin or PINK1 mutations have produced the clinical syndrome. The patient reported by Miyakawa et al., although aged>70 years at death, had Braak stage IV LB pathology, which extends beyond what is considered iLBD. That brings us to the authors’ conclusion that their case had coincidental sporadic PD. The patient’s age at onset (61 years) was typical for sporadic PD, and it is possible the parkin phenotype had not yet -----------------------------------------------------------*Correspondence to: Dr. K. M. Doherty, Reta Lila Weston Institute of Neurological Studies, 1 Wakefield Street, London, WC1N 1PJ United Kingdom; [email protected]